Efficacy and safety of single-agent belantamab mafodotin versus pomalidomide plus low-dose dexamethasone in patients with relapsed or refractory multiple myeloma (DREAMM-3): a phase 3, open-label, randomised study.

BACKGROUND: Multiple myeloma remains incurable, and heavily pretreated patients with relapsed or refractory disease have few good treatment options. Belantamab mafodotin showed promising results in a phase 2 study of patients with relapsed or refractory multiple myeloma at second or later relapse and a manageable adverse event profile. We aimed to assess the safety and efficacy of belantamab mafodotin in a phase 3 setting. METHODS: In the DREAMM-3 open-label phase 3 study, conducted at 108 sites across 18 countries, adult patients were enrolled who had confirmed multiple myeloma (International Myeloma Working Group criteria), ECOG performance status of 0-2, had received two or more previous lines of therapy, including two or more consecutive cycles of both lenalidomide and a proteasome inhibitor, and progressed on, or within, 60 days of completion of the previous treatment. Participants were randomly allocated using a central interactive response technology system (2:1) to receive belantamab mafodotin 2·5 mg/kg intravenously every 21 days, or oral pomalidomide 4·0 mg daily (days 1-21) and dexamethasone 40·0 mg (20·0 mg if >75 years) weekly in a 28-day cycle. Randomisation was stratified by previous anti-CD38 therapy, International Staging System stage, and number of previous therapies. The primary endpoint was progression-free survival in all patients who were randomly allocated. The safety population included all randomly allocated patients who received one or more doses of study treatment. This trial is registered with ClinicalTrials.gov, NCT04162210, and is ongoing. Data cutoff for this analysis was Sept 12, 2022. FINDINGS: Patients were recruited between April 2, 2020, and April 18, 2022. As of September, 2022, 325 patients were randomly allocated (218 to the belantamab mafodotin group and 107 to the pomalidomide-dexamethasone group); 184 (57%) of 325 were male and 141 (43%) of 325 were female, 246 (78%) of 316 were White. Median age was 68 years (IQR 60-74). Median follow-up was 11·5 months (5·5-17·6) for belantamab mafodotin and 10·8 months (5·6-17·1) for pomalidomide-dexamethasone. Median progression-free survival was 11·2 months (95% CI 6·4-14·5) for belantamab mafodotin and 7·0 months (4·6-10·6) for pomalidomide-dexamethasone (hazard ratio 1·03 [0·72-1·47]; p=0·56). Most common grade 3-4 adverse events were thrombocytopenia (49 [23%] of 217) and anaemia (35 [16%]) for belantamab mafodotin, and neutropenia (34 [33%] of 102) and anaemia (18[18%]) for pomalidomide-dexamethasone. Serious adverse events occurred in 94 (43%) of 217 and 40 (39%) of 102 patients, respectively. There were no treatment-related deaths in the belantamab mafodotin group and one (1%) in the pomalidomide-dexamethasone group due to sepsis. INTERPRETATION: Belantamab mafodotin was not associated with statistically improved progression-free survival compared with standard-of-care, but there were no new safety signals associated with its use. Belantamab mafodotin is being tested in combination regimens for relapsed or refractory multiple myeloma. FUNDING: GSK (study number 207495).

Non-random distribution of deleterious mutations in the DNA and protein-binding domains of IRF6 are associated with Van Der Woude syndrome.

BACKGROUND: The development of the face occurs during the early days of intrauterine life by the formation of facial processes from the first Pharyngeal arch. Derangement in these well-organized fusion events results in Orofacial clefts (OFC). Van der Woude syndrome (VWS) is one of the most common causes of syndromic cleft lip and/or palate accounting for 2% of all cases. Mutations in the IRF6 gene account for 70% of cases with the majority of these mutations located in the DNA-binding (exon 3, 4) or protein-binding domains (exon 7-9). The current study was designed to update the list of IRF6 variants reported for VWS by compiling all the published mutations from 2013 to date as well as including the previously unreported VWS cases from Africa and Puerto Rico. METHODS: We used PubMed with the search terms; "Van der Woude syndrome," "Popliteal pterygium syndrome," "IRF6," and "Orofacial cleft" to identify eligible studies. We compiled the CADD score for all the mutations to determine the percentage of deleterious variants. RESULTS: Twenty-one new mutations were identified from nine papers. The majority of these mutations were in exon 4. Mutations in exon 3 and 4 had CADD scores between 20 and 30 and mutations in exon 7-9 had CADD scores between 30 and 40. The presence of higher CADD scores in the protein-binding domain (exon 7-9) further confirms the crucial role played by this domain in the function of IRF6. In the new cases, we identified five IRF6 mutations, three novel missense mutations (p.Phe36Tyr, p.Lys109Thr, and p.Gln438Leu), and two previously reported nonsense mutations (p.Ser424*and p.Arg250*). CONCLUSION: Mutations in the protein and DNA-binding domains of IRF6 ranked among the top 0.1% and 1% most deleterious genetic mutations, respectively. Overall, these findings expand the range of VWS mutations and are important for diagnostic and counseling purposes.

CALLA: Efficacy and safety of concurrent and adjuvant durvalumab with chemoradiotherapy versus chemoradiotherapy alone in women with locally advanced cervical cancer: a phase III, randomized, double-blind, multicenter study.

BackgroundConcurrent chemoradiotherapy is the standard of care for locally advanced cervical cancer. Concurrent chemoradiotherapy with programmed blockade of the cell death-1/programmed cell death-ligand 1 pathway may promote a more immunogenic environment through increased phagocytosis, cell death, and antigen presentation, leading to enhanced immune-mediated tumor surveillance. PRIMARY OBJECTIVE: The CALLA trial is designed to determine the efficacy and safety of the programmed cell death-ligand 1 blocking antibody, durvalumab, with and following concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in women with locally advanced cervical cancer. STUDY HYPOTHESIS: Durvalumab concurrent with and following concurrent chemoradiotherapy will improve progression-free survival in patients with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IB2 to IVA cervical cancer compared with concurrent chemoradiotherapy alone. TRIAL DESIGN: CALLA is a phase III, randomized, multicenter, international, double-blind, placebo-controlled study. Patients will be randomized 1:1 to receive either durvalumab (1500 mg intravenously (IV)) or placebo every 4 weeks for 24 cycles. All patients will receive external beam radiotherapy with cisplatin (40 mg/m2) IV or carboplatin (area under the curve 2) IV once a week for 5 weeks, followed by image-guided brachytherapy. MAJOR INCLUSION/EXCLUSION CRITERIA: The study will enroll immunotherapy-naïve adult patients with histologically confirmed cervical adenocarcinoma, cervical squamous, or adenosquamous carcinoma FIGO 2009 stages IB2-IIB node positive and stage IIIA-IVA with any node stage. Patients will have had no prior definitive surgical, radiation, or systemic therapy for cervical cancer. PRIMARY ENDPOINT: The primary endpoint is progression-free survival (assessed by the investigator according to Response Evaluation Criteria in Solid Tumors v1.1, histopathological confirmation of local tumor progression or death). SAMPLE SIZE: Approximately 714 patients will be randomized 1:1 to receive either durvalumab + concurrent chemoradiotherapy or placebo + concurrent chemoradiotherapy. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Patient enrollment is continuing globally with an estimated completion date of April 2024. TRIAL REGISTRATION: NCT03830866.

AZD1775 Increases Sensitivity to Olaparib and Gemcitabine in Cancer Cells with p53 Mutations.

Tumor suppressor p53 is responsible for enforcing cell cycle checkpoints at G1/S and G2/M in response to DNA damage, thereby allowing both normal and tumor cells to repair DNA before entering S and M. However, tumor cells with absent or mutated p53 are able to activate alternative signaling pathways that maintain the G2/M checkpoint, which becomes uniquely critical for the survival of such tumor cells. We hypothesized that abrogation of the G2 checkpoint might preferentially sensitize p53-defective tumor cells to DNA-damaging agents and spare normal cells with intact p53 function. The tyrosine kinase WEE1 regulates cdc2 activity at the G2/M checkpoint and prevents entry into mitosis in response to DNA damage or stalled DNA replication. AZD1775 is a WEE1 inhibitor that overrides and opens the G2/M checkpoint by preventing WEE1-mediated phosphorylation of cdc2 at tyrosine 15. In this study, we assessed the effect of AZD1775 on endometrial and ovarian cancer cells in the presence of two DNA damaging agents, the PARP1 inhibitor, olaparib, and the chemotherapeutic agent, gemcitabine. We show that AZD1775 alone is effective as a therapeutic agent against some p53 mutated cell models. Moreover, the combination of AZD1775 with olaparib or gemcitabine is synergistic in cells with mutant p53 and constitutes a new approach that should be considered in the treatment of advanced and recurrent gynecologic cancer.

A system to identify inhibitors of mTOR signaling using high-resolution growth analysis in Saccharomyces cerevisiae.

The mechanistic target of rapamycin (mTOR) is a central regulator of growth and proliferation and mTOR inhibition is a promising therapy for a variety of diseases and disorders. Inhibition of mTOR complex I (mTORC1) with rapamycin delays aging and increases healthy longevity in laboratory animals and is used clinically at high doses to prevent organ transplant rejection and to treat some forms of cancer. Clinical use of rapamycin is associated with several unwanted side effects, however, and several strategies are being taken to identify mTORC1 inhibitors with fewer side effects. We describe here a yeast-based growth assay that can be used to screen for novel inhibitors of mTORC1. By testing compounds using a wild-type strain and isogenic cells lacking either TOR1 or FPR1, we can resolve not only whether a compound is an inhibitor of mTORC1 but also whether the inhibitor acts through a mechanism similar to rapamycin by binding Fpr1. Using this assay, we show that rapamycin derivatives behave similarly to rapamycin, while caffeine and the ATP competitive inhibitors Torin 1 and GSK2126458 are mTORC1 inhibitors in yeast that act independently of Fpr1. Some mTOR inhibitors in mammalian cells do not inhibit mTORC1 in yeast, and several nutraceutical compounds were not found to specifically inhibit mTOR but resulted in a general inhibition of yeast growth. Our screening method holds promise as a means of effectively assaying drug libraries for mTOR-inhibitory molecules in vivo that may be adapted as novel treatments to fight diseases and extend healthy longevity.

Shifting Autologous Breast Reconstruction into an Ambulatory Setting: Patient-Reported Quality of Recovery.

BACKGROUND: As bundled payment models gain popularity, it is imperative that providers use patient outcomes and patient experience to define evidence-based pathways of care. The purpose of this study was to evaluate the quality of recovery experienced by women undergoing early discharge (<24 hours) after autologous breast reconstruction with a pedicled flap and determine predictors of postoperative quality of recovery. METHODS: A prospective cohort study was performed on all women undergoing autologous breast reconstruction at Women's College Hospital between September of 2011 and July of 2013 that met study inclusion criteria. The patient-reported Quality of Recovery-27 questionnaire was used to measure quality of recovery on postoperative days 1, 2, 4, and 7. Preoperative and postoperative day 7 Quality of Recovery-27 questionnaire scores were compared. A multivariable random effect model for longitudinal data was used to evaluate any relationship between postoperative Quality of Recovery-27 questionnaire scores and American Society of Anesthesiologists classification, body mass index, and pain. Secondary analyses of delayed discharge (>24 hours) and complications were also undertaken. RESULTS: Forty women, aged 28 to 69 years, were included in this study. There was no statistically significant difference between the preoperative and postoperative day 7 Quality of Recovery-27 questionnaire scores, suggesting that our patients recovery to their preoperative state by postoperative day 7. Poorer total Quality of Recovery-27 questionnaire scores were associated with higher American Society of Anesthesiologists classification, low and high body mass indexes (U-shaped relationship), and higher pain scores. CONCLUSION: Patients undergoing an ambulatory pathway of care for autologous breast reconstruction demonstrate acceptable quality of recovery. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Surgical safety checklist: implementation in an ambulatory surgical facility.

PURPOSE: In 2007, the World Health Organization created a Surgical Safety Checklist (SSC) that encompassed a simple set of surgical safety standards. The threefold purpose of this study was to add ambulatory-specific items to the SSC, to introduce the items into an ambulatory surgical facility, and to determine if patient outcomes regarding postoperative pain and nausea/vomiting improved following implementation. In addition, safety attitudes, antibiotic timing, regional anesthesia/nerve blocks, preemptive pain medications, prophylactic antiemetics, length of stay, and hospital admission were also assessed. METHODS: After Research Ethics Board approval, staff complete a Safety Attitudes Questionnaire. Seven items were added to the SSC. Data were then collected on 180 surgical cases before SSC implementation and 195 cases following implementation. Compliance with each section of the SSC was assessed. RESULTS: On postoperative day one, the median (97.5% confidence interval [CI]) difference between pre- and post-implementation pain scores was 0.5 (97.5% CI, 0 to 1; P = 0.13), and the median difference in the rate of post-discharge nausea/vomiting was -8.4% (97.5% CI, -17.9 to 1.1; P = 0.06). There was no improvement in safety attitudes or any of the secondary outcomes, with the exception of the use of preemptive pain medications. Compliance with the three sections of the checklist, i.e., briefing, time out, and debriefing was 99.49%, 97.95%, and 96.92%, respectively. There was low compliance in verbalization of the added "ambulatory-specific items". CONCLUSION: Potential reasons for lack of uptake and integration include poor "user" buy-in, an overly lengthy checklist, and lack of prioritization of ambulatory-specific items. A shortened SSC was developed based on the results of this study. This trial was registered at ClinicalTrials.gov ID: NCT00934310.

Pharmacokinetics of cladribine in a rat model following subcutaneous and intra-arterial injections.

Male Sprague Dawley rats (n = 6-8 per group) weighing from 300-450 g were used for the study. Each rat received a single dose of cladribine (CdA) by ia (1 mg/kg) or s.c. (2 mg/kg) injection. Pharmacokinetic data were calculated by standard procedures assuming a 2-compartment open model following i.v. bolus using WinNonLin and Rstrips, and differences between the two modes of injections were considered significance when p < 0.05. The results showed that plasma concentrations of CdA decreased rapidly following a biphasic decline after both ia and s.c. administrations. The AUC and t1/2 beta after a single 1 mg/kg ia and 2 mg/kg s.c. injection of CdA were 0.66 +/- 0.34 vs 1.2 +/- 0.3 microg x h/ml and 3.5 +/- 2.1 vs 4.5 +/- 2.2 h, respectively (p > 0.05). The mean absolute bioavailability following the s.c. injection was close to 90%. The inter-subject variability of plasma concentrations of CdA was 35% and 150% following sc and ia injections, respectively. It is concluded that the rat is a reasonably good animal model to study the pharmacokinetics of CdA in plasma, and that sc injection may produce more favourable pharmacokinetic profiles than ia injection following a single dose.

Development and validation of a sensitive and specific HPLC assay of cladribine for pharmacokinetics studies in rats.

PURPOSE: To develop and validate a sensitive and specific HPLC assay for cladribine (CdA) in plasma for pharmacokinetic studies in rats. METHODS: CdA and the internal standard AZT were purchased from Sigma-Aldrich Chem. The HPLC system consisted of a Shimadzu LC-9A pump, a 3 im, 250 x 2.0 mm I.D. high speed C18 column (Jupitertrade mark), preceded by a 5 im 4 4 mm I.D. C18 guard column (Licrocarttrade mark), an Agilent Model 1050 UV-VIS detector and a 3395 Integrator. The mobile phase was made up of 0.01M KH2PO4 (pH 5): methanol: acetonitrile 90:5:5). The system was operated at ambient temperature with a flow rate of 0.3 mL/min, and UV wavelength at 265 nm, and an operating pressure of ca. 1.56 kpsi. Extraction of cladribine and AZT from plasma was achieved by solid phase extraction using 100 mg/mL C18 SPE columns Extra-septrade mark). The assay was validated for sensitivity, precision, specificity and application for pharmacokinetic study in rats. RESULTS: Under these conditions, the average retention times of CdA and AZT were 13.5 and 21 min, respectively, and recoveries were between 80 - 95%. Standard curve constructed from plasma standards was linear from 0.1 ug/mL to 1 ug/mL with regression coefficient (r2) 0.99 or greater. Sensitivity assessed by on column injection was < 1 ng. Using a 50-uL plasma sample size, the mean intra assay variations 0.1 ug/mL were 7%, and inter assay variations over a period of 3 months for 5 separate batches were less than 20%. The assay was used to study a single dose pharmacokinetic study of CdA in rats after a 2 mg/kg subcutaneous injection. CONCLUSION: The described HPLC assay has adequate sensitivity and specificity to study pharmacokinetics of CdA in rats, and could be adapted also to clinical pharmacokinetic studies.

Helicobacter pylori and infantile hypertrophic pyloric stenosis: is there a possible relationship?

BACKGROUND: Recently, it has been suggested that Helicobacter pylori might be a cause of some cases of infantile hypertrophic pyloric stenosis (IHPS) in infancy on the basis of its epidemiologic and clinical features. We performed this study to evaluate the possible relationship between IHPS and H. pylori. DESIGN: In consecutive infants with IHPS, we performed upper gastrointestinal endoscopy with biopsy before pyloromyotomy. The endoscopic appearance of the pylorus was noted to validate endoscopic features of IHPS. RESULTS: Sixteen infants, 15 male, 14 white, mean age 42 days, range 21 to 104 days, were studied. The index case had chronic active gastritis on biopsy with organisms suspicious for H. pylori. Four others had chronic active gastritis, six more had focal or mild chronic gastritis, five were normal, and none had H. pylori on histology or immune histochemical staining in selected cases. All patients had negative rapid urease test. Most common endoscopic findings of IHPS were thickened prominent asymmetric pyloric folds and pin-hole pylorus that could not be intubated by the pediatric endoscope. CONCLUSION: H. pylori was not specifically identified in our patients with IHPS. The presence of H. pylori-like organisms in the gastric mucosa in our index case and finding of chronic active gastritis in several others may indicate the possibility of an acquired infectious etiology for IHPS.